Wei Xu, PhD

Position title: Professor, Oncology

Email: wxu@oncology.wisc.edu

Website: Website

Phone: (608) 265-5540

7457 Wi Institute Medical Research
1111 Highland Ave
Madison, WI 53705

Organ System/Disease Focus
Mesenchymal stem cell lineage-specific differentiation, osteoporesis
Aligned Research Focus
basic stem cell science, tissue engineering of bone
Wei Xu headshot


Research Description

Human mesenchymal stromal cells (hMSC) can differentiate into adipocytes, osteoblasts and chondrocytes, thus have enormous therapeutic potential in regenerative medicine [1]. However, the epigenetic and transcription regulatory mechanism in stem cell fate determination and differentiation requires elucidation [2]. Co-activator associated arginine methyltransferase 1 (CARM1) has emerged as an important epigenetic regulator for pluripotency and differentiation of stem cells [3]. CARM1 catalyzes active histone modification at H3R17. In studying H3R17me2 mediated gene activation mechanism, we discovered that H3R17me2 recruits Ctr9, the scaffold subunit of RNA polymerase II-associated factor complex (PAFc) as “reader” protein [4]. A genome-wide association study identified Ctr9 as a candidate gene involved in osteoporosis in Kashin-Beck disease patients [5]. To study if Ctr9 plays a role in MSC lineage differentiation, we knocked down (KD) Ctr9 in human MSCs followed by induction of multi-lineage differentiation. Our results showed that osteogenic differentiation (OD) was blocked, whereas adipogenic and chondrocyte differentiation were not affected by loss of Ctr9. Restoration of Ctr9 in hMSC rescued OD, and exogenous expression of Ctr9 augments OD, indicating a dose-dependent effect of Ctr9 in promoting OD. Further studies in Xu lab will determine the mechanism by which CARM1-H3R17me2-Ctr9 axis functionally regulates MSC cell lineage differentiation.

Selected References:
  • Chan N. T., Huang, J., Ma, G., Zeng, H., Donahue, K., Wang, Y., Li, L. and Xu, W. (2022) The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium, Nucleic Acid Research, 50: 1969-1992. PMID: 35137163
  • Kim E.J., Liu, P., Zhang, S., Wang, Y., Schehr, J., Wolfe, S., Dickerson, A., Donahue, K., Lu, L., Rui, L.X., Zhong, X., Wisinski, K., Yu, M., Suzuki, A., Lang, J.M., Ong, I., Xu, W. (2021) BAF155 methylation drives triple-negative breast cancer metastasis by hijacking super-enhancers and subverting anti-tumor immunity, Nucleic Acid Research, 49 (21): 12211-12233. PMID: 34865122
  • Liu F.B., Ma F., Wang Y., Hao L., Zeng, H., Jia, C., Liu, P., Ong, I., Li, B., Chen G., Jiang, J., Wang, Y., Gong, S., Li, L., and Xu, W. (2017) PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis, Nature Cell Biology, 19: 1358-1370. PMID: 29058718
  • Shishkova E., Zeng, H., Liu, F., Kwiecien, N., Hebert, A. S., Coon, J., and Xu, W. (2017) Global mapping of CARM1 substrate defines enzyme specificity and substrate recognition. Nature Communications8: 15571. PMID: 28537268
  • Wang, L., Zhao, Z., Meyer, M. B., Saha, S., Yu, M., Guo, A., Wisinski, K. B., Huang, W., Cai, W., Pike, J. W., Yuan, M., Ahlquist, P., and Xu, W. (2014) CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis.  Cancer Cell, 25(1):  21-36, PMCID:  PMC4004525
  • Zeng, H. and Xu, W. (2015) Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERa-positive breast tumorigenesis. Genes & Development, 29: 2153-2167.  PMCID:  PMC4617979
  • Wu, J., and Xu, W. (2012) Histone H3R17me2a Mark Recruits Human RNA Polymerase-Associated Factor 1 Complex to Activate Transcription.  Proc. Natl. Acad. Sci. USA, 109:  5675-5680, PMCID:  PMC3326481